CN105377855B - 合成双氢青蒿素及青蒿素衍生物的方法和装置 - Google Patents
合成双氢青蒿素及青蒿素衍生物的方法和装置 Download PDFInfo
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- CN105377855B CN105377855B CN201480040034.1A CN201480040034A CN105377855B CN 105377855 B CN105377855 B CN 105377855B CN 201480040034 A CN201480040034 A CN 201480040034A CN 105377855 B CN105377855 B CN 105377855B
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title claims abstract description 390
- 229960002521 artenimol Drugs 0.000 title claims abstract description 97
- 238000000034 method Methods 0.000 title claims abstract description 68
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 title abstract 5
- 229930016266 dihydroartemisinin Natural products 0.000 title abstract 5
- 230000002194 synthesizing effect Effects 0.000 title description 3
- 229930101531 artemisinin Natural products 0.000 claims abstract description 231
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 193
- 239000007787 solid Substances 0.000 claims abstract description 167
- 239000012190 activator Substances 0.000 claims abstract description 90
- PLQMEXSCSAIXGB-SAXRGWBVSA-N Arteannuic acid Natural products C1=C(C)CC[C@H]2[C@H](C)CC[C@@H](C(=C)C(O)=O)[C@H]21 PLQMEXSCSAIXGB-SAXRGWBVSA-N 0.000 claims abstract description 78
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 70
- 150000004678 hydrides Chemical class 0.000 claims abstract description 67
- 238000004519 manufacturing process Methods 0.000 claims abstract description 27
- PLQMEXSCSAIXGB-UHFFFAOYSA-N artemisininic acid Natural products C1=C(C)CCC2C(C)CCC(C(=C)C(O)=O)C21 PLQMEXSCSAIXGB-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 16
- 229930183339 qinghaosu Natural products 0.000 claims description 208
- 239000000203 mixture Substances 0.000 claims description 120
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 115
- 239000002585 base Substances 0.000 claims description 113
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 claims description 106
- 239000002253 acid Substances 0.000 claims description 98
- -1 cationic ion salt Chemical class 0.000 claims description 97
- 229910052739 hydrogen Inorganic materials 0.000 claims description 93
- 239000001257 hydrogen Substances 0.000 claims description 93
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 91
- 239000000463 material Substances 0.000 claims description 83
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 70
- 150000007513 acids Chemical class 0.000 claims description 69
- 229910052760 oxygen Inorganic materials 0.000 claims description 56
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 51
- 239000001301 oxygen Substances 0.000 claims description 51
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 50
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 46
- 238000007539 photo-oxidation reaction Methods 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 34
- OKTJSMMVPCPJKN-UHFFFAOYSA-N activated carbon Substances [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 22
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 21
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 21
- 238000005336 cracking Methods 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000000945 filler Substances 0.000 claims description 17
- 230000001404 mediated effect Effects 0.000 claims description 16
- 239000002243 precursor Substances 0.000 claims description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 13
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002105 nanoparticle Substances 0.000 claims description 12
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 11
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052593 corundum Inorganic materials 0.000 claims description 8
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 235000001405 Artemisia annua Nutrition 0.000 claims description 7
- 240000000011 Artemisia annua Species 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 6
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 claims description 6
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 5
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 4
- 229910006069 SO3H Inorganic materials 0.000 claims description 4
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 4
- 150000004692 metal hydroxides Chemical class 0.000 claims description 4
- 229920000767 polyaniline Polymers 0.000 claims description 4
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 229910002788 Ru-CeO2 Inorganic materials 0.000 claims description 3
- 229910019891 RuCl3 Inorganic materials 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- ZASWJUOMEGBQCQ-UHFFFAOYSA-L dibromolead Chemical compound Br[Pb]Br ZASWJUOMEGBQCQ-UHFFFAOYSA-L 0.000 claims description 3
- FPHIOHCCQGUGKU-UHFFFAOYSA-L difluorolead Chemical compound F[Pb]F FPHIOHCCQGUGKU-UHFFFAOYSA-L 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000000017 hydrogel Substances 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- HWSZZLVAJGOAAY-UHFFFAOYSA-L lead(II) chloride Chemical compound Cl[Pb]Cl HWSZZLVAJGOAAY-UHFFFAOYSA-L 0.000 claims description 3
- RQQRAHKHDFPBMC-UHFFFAOYSA-L lead(ii) iodide Chemical compound I[Pb]I RQQRAHKHDFPBMC-UHFFFAOYSA-L 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 239000002071 nanotube Substances 0.000 claims description 3
- NUOYUAPJNWWWTI-UHFFFAOYSA-N oxygen(2-) sulfuric acid zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4].OS(O)(=O)=O NUOYUAPJNWWWTI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001553 phloroglucinol Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 3
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical compound OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical compound [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- 229910005948 SO2Cl Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 2
- 239000000920 calcium hydroxide Substances 0.000 claims 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 2
- 229910052737 gold Inorganic materials 0.000 claims 2
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- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims 2
- 229910052707 ruthenium Inorganic materials 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
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- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims 1
- 150000001983 dialkylethers Chemical class 0.000 claims 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 71
- 229960004191 artemisinin Drugs 0.000 abstract description 28
- 230000009467 reduction Effects 0.000 abstract description 23
- 238000010924 continuous production Methods 0.000 abstract description 2
- JYGAZEJXUVDYHI-DGTMBMJNSA-N dihydroartemisinic acid Chemical compound C1CC(C)=C[C@@H]2[C@H]([C@@H](C)C(O)=O)CC[C@@H](C)[C@@H]21 JYGAZEJXUVDYHI-DGTMBMJNSA-N 0.000 abstract 4
- JYGAZEJXUVDYHI-UHFFFAOYSA-N dihydroartemisininic acid Natural products C1CC(C)=CC2C(C(C)C(O)=O)CCC(C)C21 JYGAZEJXUVDYHI-UHFFFAOYSA-N 0.000 abstract 2
- 239000007858 starting material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 233
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 217
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- 235000019441 ethanol Nutrition 0.000 description 99
- 235000019439 ethyl acetate Nutrition 0.000 description 87
- 239000012074 organic phase Substances 0.000 description 87
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 71
- 238000006243 chemical reaction Methods 0.000 description 70
- 229910052799 carbon Inorganic materials 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 230000036541 health Effects 0.000 description 57
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 52
- 239000000741 silica gel Substances 0.000 description 49
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 46
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- 239000007864 aqueous solution Substances 0.000 description 45
- 229920000642 polymer Polymers 0.000 description 45
- 238000010079 rubber tapping Methods 0.000 description 45
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical group FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 44
- 125000001424 substituent group Chemical group 0.000 description 42
- 238000001819 mass spectrum Methods 0.000 description 41
- 241000209094 Oryza Species 0.000 description 40
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- 235000009566 rice Nutrition 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 37
- 235000017557 sodium bicarbonate Nutrition 0.000 description 33
- 239000002904 solvent Substances 0.000 description 30
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical class COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 27
- 238000006722 reduction reaction Methods 0.000 description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 25
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 20
- 230000033001 locomotion Effects 0.000 description 19
- NLYNIRQVMRLPIQ-XQLAAWPRSA-N artemotil Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OCC)O[C@H]4[C@]32OO[C@@]1(C)O4 NLYNIRQVMRLPIQ-XQLAAWPRSA-N 0.000 description 18
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
- 150000002432 hydroperoxides Chemical group 0.000 description 16
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 description 15
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- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
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- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 10
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- 0 C[C@](CCC1C(C)=C(O)O[C@@]2O[C@@](C)CC3)C3[C@@]12O* Chemical compound C[C@](CCC1C(C)=C(O)O[C@@]2O[C@@](C)CC3)C3[C@@]12O* 0.000 description 9
- UVNHKOOJXSALHN-ILQPJIFQSA-N artelinic acid Chemical compound O([C@@H]1[C@H](C)[C@@H]2CC[C@H]([C@@H]3CC[C@]4(C)O[C@H]([C@]23OO4)O1)C)CC1=CC=C(C(O)=O)C=C1 UVNHKOOJXSALHN-ILQPJIFQSA-N 0.000 description 9
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- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical class ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 1
- QFYXSLAAXZTRLG-UHFFFAOYSA-N pyrrolidine-2,3-dione Chemical class O=C1CCNC1=O QFYXSLAAXZTRLG-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- VATDYQWILMGLEW-UHFFFAOYSA-N sec-butyllithium Chemical compound [Li]C(C)CC VATDYQWILMGLEW-UHFFFAOYSA-N 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 125000005310 triazolidinyl group Chemical group N1(NNCC1)* 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc oxide Inorganic materials [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/245—Stationary reactors without moving elements inside placed in series
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/24—Stationary reactors without moving elements inside
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13176539.8 | 2013-07-15 | ||
| EP13176539.8A EP2826779A1 (fr) | 2013-07-15 | 2013-07-15 | Procédé et appareil pour la synthèse de dihydroartémisinine et de dérivés d'artémisinine |
| PCT/EP2014/065053 WO2015007693A1 (fr) | 2013-07-15 | 2014-07-14 | Procédé et appareil de synthèse de dihydroartémisinine et de dérivés d'artémisinine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105377855A CN105377855A (zh) | 2016-03-02 |
| CN105377855B true CN105377855B (zh) | 2018-04-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480040034.1A Active CN105377855B (zh) | 2013-07-15 | 2014-07-14 | 合成双氢青蒿素及青蒿素衍生物的方法和装置 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US9802952B2 (fr) |
| EP (2) | EP2826779A1 (fr) |
| CN (1) | CN105377855B (fr) |
| AP (1) | AP2016009026A0 (fr) |
| WO (1) | WO2015007693A1 (fr) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2540365B (en) * | 2015-07-14 | 2019-12-11 | Thermo Fisher Scient Bremen Gmbh | Control of gas flow |
| EP3210667A1 (fr) | 2016-02-29 | 2017-08-30 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Dispositif à écoulement modulaire continu |
| CN107383048B (zh) * | 2017-08-11 | 2019-09-03 | 昆药集团股份有限公司 | 一种青蒿素类衍生物、其合成及应用 |
| CN112705149B (zh) * | 2019-10-25 | 2022-10-21 | 中国石油化工股份有限公司 | 一种内衬石英反应器 |
| CN113801132A (zh) * | 2020-06-17 | 2021-12-17 | 重庆药友制药有限责任公司 | 一种采用连续流管道反应制备青蒿素的方法 |
| CN112694482B (zh) * | 2020-12-29 | 2022-04-01 | 张家港威胜生物医药有限公司 | 利用微通道反应器制备青蒿琥酯的方法 |
| CN114832753B (zh) * | 2022-06-08 | 2023-09-12 | 河北诚信集团有限公司 | 连续制备原甲酸酯的装置及方法 |
| CN115385929A (zh) * | 2022-09-16 | 2022-11-25 | 延边大学 | 一种二氢青蒿素类衍生物、制备方法及应用 |
| CN115738384B (zh) * | 2022-12-13 | 2024-05-28 | 中国科学院过程工程研究所 | 一种离子液体@SiO2材料选择性分离青蒿素/青蒿烯的方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887907A (zh) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | 以青蒿素为原料单反应釜法制备β-蒿乙醚的新工艺 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6750356B1 (en) | 2002-12-02 | 2004-06-15 | Council Of Scientific And Industrial Research | Single pot conversion of artemisinin into arteether |
| WO2008087666A1 (fr) | 2007-01-19 | 2008-07-24 | Almet Corporation | Procédé de préparation d'un dérivé éther de l'artémisinine |
| WO2008087667A1 (fr) | 2007-01-19 | 2008-07-24 | Almet Corporation | Procédé de préparation d'artésunate à partir d'artémisinine |
| CN103764660B (zh) | 2011-08-29 | 2016-08-24 | 马普科技促进协会 | 用于合成青蒿素的方法和装置 |
| GB2494676A (en) * | 2011-09-15 | 2013-03-20 | Univ Warwick | Reduction of artemisinin to dihydroartemisinin and suitable apparatus |
-
2013
- 2013-07-15 EP EP13176539.8A patent/EP2826779A1/fr not_active Withdrawn
-
2014
- 2014-07-14 US US14/904,671 patent/US9802952B2/en active Active
- 2014-07-14 WO PCT/EP2014/065053 patent/WO2015007693A1/fr active Application Filing
- 2014-07-14 EP EP14738842.5A patent/EP3022208B1/fr active Active
- 2014-07-14 AP AP2016009026A patent/AP2016009026A0/en unknown
- 2014-07-14 CN CN201480040034.1A patent/CN105377855B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102887907A (zh) * | 2011-07-22 | 2013-01-23 | 江苏斯威森生物医药工程研究中心有限公司 | 以青蒿素为原料单反应釜法制备β-蒿乙醚的新工艺 |
Non-Patent Citations (1)
| Title |
|---|
| 正交实验法研究双氢青蒿素的制备工艺;江剑芳等;《应用化工》;20081031;第37卷(第10期);1175-1178 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2015007693A1 (fr) | 2015-01-22 |
| EP2826779A1 (fr) | 2015-01-21 |
| EP3022208B1 (fr) | 2017-06-14 |
| US9802952B2 (en) | 2017-10-31 |
| EP3022208A1 (fr) | 2016-05-25 |
| US20160145265A1 (en) | 2016-05-26 |
| AP2016009026A0 (en) | 2016-02-29 |
| CN105377855A (zh) | 2016-03-02 |
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